D-amino acid oxidase (DAAO), a flavoenzyme expressed in the mammalian liver, kidneys, and brain, catalyzes the oxidative deamination of D-amino acids. The physiological role of DAAO in the kidney and liver is detoxification of accumulated D-amino acids. DAAO and the D-amino acids that this enzyme regulates have been implicated in a variety of physiological processes. For example, D-aspartate regulates hormone release, D-arginine affects pathways that regulate arterial pressure, and elevated D-alanine content has been found in the gray matter of Alzheimer's patients. In addition, D-serine has been found to play an important role as a neurotransmitter in the human central nervous system by binding to the N-methyl D-aspartate (NMDA) receptor as an agonist at the glycine site. This observation suggests that D-serine plays a broad role in synaptic events associated with development, plasticity, learning, memory and excitotoxicity.
Cumulative evidence suggests that allosteric activation of the NMDA receptor through the glycine modulatory site provides new therapeutic potential for treating cognitive-related disorders, such as schizophrenia. D-Serine, an endogenous agonist at the glycine modulatory site, has been shown to be effective in treating positive, negative, and cognitive symptoms of schizophrenia in clinical studies. Despite encouraging clinical data, clinical development of D-serine likely will face obstacles, in part, because of the high dosages required for efficacy. This requirement is primarily due to the substantial metabolism of peripherally administered D-serine by DAAO. DAAO-mediated metabolism of D-serine not only limits the bioavailability of D-serine, but it also has the potential to induce kidney toxicity (nephrotoxicity) through the generation of hydrogen peroxide. Compounds capable of blocking or inhibiting DAAO-mediated D-serine metabolism, which could substantially lower the dosages required for efficacy while preventing hydrogen peroxide-induced peripheral toxicity, could be useful for treating schizophrenia.